I. To understand the mechanisms by which the thyroid hormone, 3, 3', 5-triiodo-L-thyronine (T3), promotes growth, differentiation and development, we have been studying the structure, function and regulation of the human beta1 thyroid hormone receptor (h-TRbeta1). (a) One critical question is how the tissue-specific expression of TRs is regulated. Using okadaic acid (OA) as a tool, we found that activation of the phosphorylation of TRbeta1 led to an induction of its expression which was not found in TR subtype beta2 or alpha1 (TRalpha1). Furthermore, the OA-induced TRb1 expression is cell-type dependent. This induction was due to an increase in the stability of TRb1 protein conferred by phosphorylation. This is the first report to indicate that one of the mechanisms by which the TR isoforms are differentially expressed is via the tissue-specific stabilization of TRb1. (b) The transcriptional activity of TRs is T3-dependent. We carried out mutational analysis to identify the site(s) in TRb1 which are critical to this function. We identified Glu252 as an important residue in transmitting the hormonal signal from the T3 binding domain to the DNA binding domain to affect the gene regulating activity of TRb1. These findings have advanced our understanding of the molecular basis of T3-dependent transcriptional activation. (c) It is unclear whether the two TR isoforms, TRa1 and TRb1, have differential biological activities. We constructed a series of chimeric TRs in which the different domains were sequentially interchanged and their DNA binding activities were evaluated. For the first time, we found that the two TR isoforms have differential activities which were mediated by interplay of their domains. This serves as an important regulatory mechanism to achieve diversity and specificity of pleiotropic T3 effect. II. To understand the molecular basis of the genetic disease, resistance to thyroid hormones (RTH), we evaluated the nature and role of the wild type TRb1 (wTRb1) mutant heterodimers in RTH. We found that there was a strong correlation between the formation of TRb1/mutant and the dominant negative potency of mutants. Thus, wTRb1/mutant heterodimers could play an important role in RTH.